PROJECT SUMMARY Virtually all sensory information enters the neocortex by way of the thalamus. The neocortex, in turn, sends a massive projection back to the thalamus. Despite being reciprocally connected partners, we are only beginning to understand the nature of cortex's influence over the thalamus. It is clear that the coordinated activities of these two areas are essential for normal sensation, movement, and cognition. Moreover, altered communication between the thalamus and the neocortex has been associated with certain neuropsychiatric disorders, such as epilepsy and schizophrenia. The central goal of this proposal is to understand the dynamic nature and mechanisms underlying layer six corticothalamic circuit activity. There are three specific aims: 1) the activity- dependent influence of corticothalamic output on the excitability and sensory-evoked responses of aligned thalamic neurons will be characterized in detail using optogenetic and electrophysiological methods in an intact preparation in vivo; 2) the impact of wakefulness on the activity-dependent influence of corticothalamic output will be tested within distinct waking states using awake, head-restrained mice; 3) the hypothesis that higher- order inputs gate corticothalamic circuit activity will be tested in both isolated and intact brain preparations. Relevance: This investigation will provide important new insight into the function of the layer six corticothalamic system. Ultimately, this information will be essential for our mechanistic understanding of many normal brain functions as well as certain pathophysiological disorders involving communication between the neocortex and the thalamus.